Protein kinase is an enzyme that catalyzes the phosphorylation of a hydroxyl group positioned at the tyrosine, serine, and threonine residues in proteins, and plays an important role in transducing growth factor signals that cause the growth, differentiation, and proliferation of cells.
In order to maintain the homeostasis of an organism, the in vivo signal transduction system needs to smoothly keep a balance between on and off. However, the mutation or overexpression of a specific protein kinase disrupts the signal transduction system in normal cells (usually in a state where the in vivo signal transduction is continued), thereby causing various diseases such as cancer, inflammation, metabolic disease, and disease of the brain. Examples of a representative protein kinase causing an abnormal cell growth disease include Raf, KDR, Fms, Tie2, SAPK2a, Ret, Abl, Abl (T315I), ALK, Aurora A, Bmx, CDK/cyclinE, Kit, Src, EGFR, EphAl, FGFR3, FLT3, Fms, IGF-1R, IKKb, IR, Itk, JAK2, KDR, Met, mTOR, PDGFRa, Plk1, Ret, Syk, Tie2, TrtB, and the like. Accordingly, through development of a compound having a selective inhibitory activity against a specific kinase among various protein kinases, studies on developing a target anticancer agent have been conducted.
Meanwhile, acute myeloid leukemia (AML) is one of the fatal blood diseases, and is a disease in which blood cells are continuously proliferated while being abnormally differentiated. Fms-Like tyrosine receptor kianse-3 (FLT3) is usually expressed in a hematopoietic stem cell and a progenitor cell, and is a receptor tyrosine kinase that plays an important role in hematopoiesis. FLT3 is one of the genes that are the most frequently mutated in patients with acute myeloid leukemia. In the case of about 25% of patients with AML, FLT3 genes are mutated into FLT3-ITD, and the FLT3-ITD mutation is one of the main factors that make early diagnosis difficult. In addition to the FLT3-ITD mutation, point mutations (D835Y, D835V, and D835F) of D835 amino acid in an activation loop have been reported. These mutations are discovered in about 10% of patients with AML, and induce overactivity of FLT3 by making the inactive state of FLT3 unstable. Overactive mutations such as the FLT3-ITD and FLT3-D835 point mutations cause AML by continuously increasing lower signals related to the differentiation and proliferation of blood cells. Accordingly, AML-inducing FLT3 mutations have been drug targets in the development of an AML target therapeutic agent.
As new drug candidate materials that adopt FLT3 developed up to now as a target, lestaurtinib, sunitinib, sorafenib, quizartinib, tandutinib, and the like have entered into clinical trials. The all candidate materials have been reported to show a strong activity against FLT-ITD mutant, however, quizartinib induced resistant mutants of FLT3-ITD+F691L, FLT3-ITD+D835Y, FLT3-ITD+F691L+D835Y (triple mutants), etc. Accordingly, there is an urgent need for developing a new compound which also has inhibitory activity against drug-resistant point mutation of FLT3 as a target therapeutic agent of acute myeloid leukemia (AML).